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You will fight with tricks - with malaria

Israeli research reveals: how the deadly parasite escapes the immune system

escape with the help of a complex genetic mechanism. Malaria parasites in red blood cells. Photo courtesy of Prof. Ron Dzikowski.
escape with the help of a complex genetic mechanism. Malaria parasites in red blood cells. Photo courtesy of Prof. Ron Dzikowski.

For those who live in a developed country, it seems that malaria has already passed away from the world. Indeed, since the swamps were drained, and most of the mosquitoes were eradicated, malaria disappeared from the world. the western In the third world, on the other hand, malaria is still very common - millions get sick with it, mainly in Africa and Southeast Asia, and about a million people die from malaria every year, mostly toddlers and pregnant women. The huge disparity in morbidity between the regions is also due to climatic reasons, it is much more difficult to exterminate mosquitoes in tropical regions where there is an abundance of precipitation and high temperatures all year round (necessary for the development of mosquitoes), but mainly for economic reasons. In countries that are not developed, there are fewer means to establish efficient infrastructures for draining swamps, it is more difficult to establish an orderly system for the extermination of mosquitoes, and above all there is not enough investment of resources in the development of new and effective medicines or vaccines for malaria. It is likely that the disease would have killed hundreds of thousands in the US and Western Europe every year, there had long been an effective vaccine against it. Today there are several effective malaria prevention drugs that are given to tourists before coming to an infected area. However, treating the residents with these drugs on a large scale is not on the agenda, both in terms of the high cost and mainly because the malaria parasites quickly develop resistance to the drugs, a process that will occur at an even higher speed as the use of the drug expands, which will of course result in the loss of the effectiveness of the drug within a short period of time from the start of its use . Therefore, scientists are unanimous that the effective solution against malaria is the development of a vaccine. In order to be able to implement it, the vaccine must be easy to use even in difficult conditions (for example, it does not require freezing), effective in the long term (because it is much more difficult to manage repeated vaccination operations and medical follow-up in the third world), and above all - cheap. These requirements only increase the challenge for scientists trying to develop a malaria vaccine, but the main challenge in developing such a vaccine is dealing with one of the most complex – and fascinating – biological systems that have evolved in nature.

Blood, saliva and bites
The cause of malaria is a single-celled parasite called Plasmodium. Unlike bacteria or viruses, the plasmodium is a "real" cell, similar in many respects to the cells of our body. The parasite is transmitted between humans by the bites of the Anopheles mosquito. In fact, it is not a sting, but a bite - more precisely a "blood meal" of the female mosquito, which feeds on the proteins in the blood. During the meal, the mosquito injects saliva into the wound. The saliva contains numbing substances (if the bite hurts, the mosquito's chances of continuing on its way safely, without being detected), as well as anti-coagulant substances, to allow the mosquito to suck the blood without interference, will be greatly reduced. In the saliva, the malaria parasites also swim for them, and they are injected with it into the blood of the person. In a very short time (less than an hour), the parasites penetrate from the blood stream into a certain type of liver cells, and begin to quickly get confused there. A few days later, the liver cells burst from the load of parasites, and the parasites are released into the blood. A few will return and invade liver cells, but most will invade red blood cells, grow inside them as they feed on their contents, and even continue to reproduce. After a certain period of time (two or three days), the blood clot will disintegrate, and the parasites will be released from it. The vast majority of them will immediately penetrate new red blood cells and continue to multiply within them in the usual way: the parasite cells grow and divide into new cells. However, some of the parasites will go through a different process, and will develop in the red blood cells into cells capable of producing sex cells. When the red blood cells containing these cells reach the mosquito's intestines, the parasite cells sense the chemical changes around them and the drop in temperature, and begin to produce male or female parasite cells. These are released from the red blood cells, and pass through the intestines of the mosquito for sexual reproduction. After several cycles of sexual reproduction, the asexual parasites (which reproduce by normal division) also appear. They penetrate through the intestinal wall of the mosquito, and migrate to its salivary gland. From there they are injected into the blood while the mosquito eats its heart, infecting another person with malaria. Malaria causes damage to the liver, but the main damage is caused by the damage to the red blood cells and toxic substances that are created in them due to the activity of the parasite, and are released into the blood when the cells break down. Malaria symptoms include high fever, pain, and sometimes vomiting. Another phenomenon is that the parasite makes the blood cells it contains sticky - they stick to the wall of the blood vessels, which prevents them from reaching the spleen, where the immune system breaks them down. However, this infection can also create blockages in small blood vessels - and when this happens - mainly in the brain, kidneys and lungs, the damage can be fatal.

Replace proteins
The Plasmodium parasites, which cause malaria, are not a uniform group. There are hundreds of different species of Plasmodium, which cause disease in many animals. Of these, four species cause disease in humans, and one of them - Plasmodium falciparum - is the cause of most severe and dangerous disease. As mentioned, the immune system is able to attack the malaria parasites and destroy them. This is a rather complex challenge, because most forms of the parasite are most of the time inside the blood cells (or liver cells), and they are not directly exposed to the cells of the immune system. However, when the parasite is inside the red blood cells, certain of its proteins are displayed on the outside of the cells, and they are what cause them to stick to the blood vessels. These proteins can be recognized and attacked by the immune system, and it does. Unfortunately, it does this very slowly, and until the immune system manages to react - the malaria parasites multiply quickly and cause a lot of damage. Why is the immune system's response so slow? It turns out that the parasite has a way of escaping the immune system. As mentioned, certain proteins of the parasite are found on the outside of the red blood cell when it multiplies inside it. The immune system produces antibodies that recognize the foreign protein, bind to it and activate an effective immune defense against it - they mark the target for white blood cells whose job it is to break down and destroy any invader. The immune system is a learning system, and its cells are able to produce an effective antibody against any protein, even one they have never met, but this takes a few days. The parasite makes good use of these days, and by the time the antibodies arrive, it replaces the external protein with another protein that has a similar activity, but the composition is slightly different, and the antibodies produced against the original protein do not recognize it. Again a few days will pass until a suitable antibody is produced, and again the parasite changes its protein to another and slightly different version. how does he do it? The protein that causes the red blood cell to stick is not produced from a single gene, like most proteins. There is a whole family of about 60 genes that produce alternative versions of this protein, which is why the whole family of proteins is called var (short for variety). This means - the parasite can survive in the blood for many weeks and months before the immune system succeeds in eradicating it, and in the meantime it can cause a lot of damage, and even kill the patient. However, scientific knowledge about this complex system is still very little. How does the parasite activate only one gene out of dozens, while at the same time making sure that all the others remain switched off? How does it decide when to replace the expressed gene? Why does it continue to replace the active genes from time to time, even when the parasites grow in a test tube, and are not exposed to the threats of the immune system? The laboratory of Prof. Ron Dzikovski, at the School of Medicine of the Hebrew University and the Imerick Institute, is trying to provide answers to these questions.

Inbar Amit Avraham and Prof. Ron Dzikovski. Photo courtesy of Prof. Dzikowski
Inbar Amit Avraham and Prof. Ron Dzikovski. Photo courtesy of Prof. Dzikowski

Silencers and activators
In the work led by the research student, Inbar Amit Avraham, the researchers discovered that the entity responsible for the expression of a certain gene is a long RNA molecule. In most cells, the genetic material is stored in the nucleus in the form of DNA. RNA is a molecule similar to DNA, and it is usually used to create a "working copy" of DNA - when the cell produces a protein based on the DNA in the nucleus, it does not remove the original material, but creates a copy of the relevant section (in the RNA molecule), and the copy This is the one that goes to the protein production machines outside the cell nucleus. However, RNA has other uses, and in this case, controlling the activation of genes.

Many times, an external factor that binds to a certain site in the gene, activates or deactivates the expression of this gene - that is, causes it to produce RNA (and subsequently the protein) or to stop producing it. In the malaria parasite, Amit-Abraham, Dzikowski and their colleagues discovered that the control function belongs to a certain segment of RNA: when the RNA attaches to one of the dozens of var genes, only this particular protein is produced, and all other genes are silenced. The researchers not only identified the RNA molecule that activates the selected gene, but also identified the DNA that codes for it, which is a certain segment within that gene.

This allowed them to do controlled experiments: they created genetically modified parasites, in which the researchers had control over that part of the gene responsible for the production of the critical RNA. When they caused a lot of this RNA to be produced, the parasite's particular gene became active when it should have been silenced. Alternatively, preventing the expression of the RNA resulted in the paralysis of a gene that was supposed to be in an active state. In previous studies, Dzikowski and his colleagues uncovered part of the complement mechanism, and discovered several substances involved in silencing the var genes in the malaria parasite. In the new study, published recently In Bethune PNAS American Academy of Sciences, the researchers explain for the first time the mechanism that enables the activity of a certain gene, when all the others are silenced. "The findings can allow us to develop ways to act against the malaria parasite," explains Dzikowski. "We can find a way to prevent him from activating the gene he is interested in, and thus block the disease, or alternatively, force him to activate all the genes, thus preventing his ability to escape the immune system and allow it to destroy him."

save a life

The research by Dzikowski and his colleagues, which was partly funded by the Israeli National Academy of Sciences, is breaking ground towards the development of effective methods to combat malaria, however - there is still a long way to go before deciphering all the secrets of the sophisticated parasite. The researchers now know how one particular gene from the large family is activated, but they still do not know much about the control mechanism of the system: what causes the parasite to replace the active gene at a given time, how the parasite knows how to regulate the activity of the genes (and not activate, for example, the same gene twice in a short time), and how - if at all - the coordination between the parasite cells takes place - so that they activate the same genes at the same time, and do not expose their friends to the activity of the immune system. Thanks to the latest achievements, the laboratory received a large research grant from the European Union, to allow researchers to take advantage of their knowledge of the complex mechanisms of malaria, and develop a vaccine that could save the lives of hundreds of thousands of people.

More of the topic in Hayadan:

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